This invention relates to a medical device which has physiological activity and can maintain its antimicrobial activity for a prolonged period of time under physiological conditions, and to a method for producing the medical device.
Proposals have been made to develop medical materials having various functions by attaching to the surface thereof enzymes, polysaccharides, coenzymes, enzyme inhibitors, hormones, antigens, antibodies and the like physiologically active substances. For example, JP-A-50-139174 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d) discloses a method in which a high molecular weight substance having hydroxyl groups is reacted with an aminoaldehyde, aminoacetal or the like to introduce amino groups into the high molecular weight substance which is then reacted with heparin. Also, JP-B-53-15913 (the term xe2x80x9cJP-Bxe2x80x9d as used herein means an xe2x80x9cexamined Japanese patent publicationxe2x80x9d) discloses a method for imparting fibrinolytic activity in which a fibrinolytic enzyme is linked to the surface of a polyamide. In addition, Japanese Patent No. 1406830 discloses a method in which enzyme activity is added to the surface of a solid material.
On the other hand, cases have been increasing in recent years in which a treatment or diagnosis is carried out by percutaneously inserting and indwelling a catheter or the like medical device into the living body. However, such procedures also cause a serious problem of inducing infectious diseases mediated by the catheter and the like medical devices. For example, a vessel catheter or a ureteral catheter is indwelt in the living body for a prolonged period of time in many cases, and bacteria invade through these catheters and frequently cause sepsis, urethritis, cystitis, pyelitis and the like symptoms. Because of this, washing of the inserting part of each medical device or injection of a germicide is carried out as a means for preventing infectious diseases caused by a catheter and the like medical devices. However, not only is such handling complex, but also the handling itself becomes a new source of infection.
Although the preventive administration of antibiotics and chemotherapeutic drugs is also carried out, it is said that unplanned chemotherapy is harmful because of the problems of inducing side effects and increasing the generation frequency of resistant strains. Also, these antibiotics and chemotherapeutic drugs are meant to be topically applied. With regard to the topical use of antibiotics and chemotherapeutic drugs, JP-B-2-25625 discloses a ureteral catheter having the ability to prevent urinary tract infection, in which antibiotics are linked through an ionic bonding to a ureteral catheter made of an olefinic polymer, a diene polymer or a silicon polymer as a raw material. JP-B-56-34203 discloses a method for producing an antimicrobial material in which a high molecular weight substance having acidic groups is allowed to react with bis-(p-chlorophenyldiguanido)-hexane or a salt thereof. Additionally, JP-W-7-501470 (the term xe2x80x9cJP-Wxe2x80x9d as used herein means an xe2x80x9cpublished Japanese national phase international patent applicationxe2x80x9d) discloses antimicrobial medical articles coated with antimicrobial substances.
In addition, an antimicrobial antithrombogenic composition which contains a fat-solubilized mucopolysaccharide of an ionic complex of a mucopolysaccharide with a quaternary ammonium or a quaternary phosphonium has also been disclosed (JP-A-10-295799, JP-A-10-179724),but it has a disadvantage in that the quaternary ammonium or quaternary phosphonium as the antimicrobial component of this case has relatively weak antimicrobial activity.
On the contrary, JP-A-10-328293 shows that a physiologically active substance and an antimicrobial activity can be added simultaneously and relatively easily independent of the base material which constitutes a medical device. When this method is used, a medical device having high degree functions can be easily obtained by binding a combination of an antimicrobial substance having relatively strong antimicrobial activity and useful substances having various physiological activities on a surface of the base material of the medical device.
Depending on the medical devices to be used in the clinical field, there are cases in which persistence of functions is required for a relatively prolonged period of time regarding their use period, and antimicrobial activity is one such function. However, in the case of the medical device and its production method disclosed in JP-A-10-328293, an antimicrobial substance is gradually released from the base material surface during use of the medical device, and the duration of antimicrobial property therefore is not sufficient in some cases depending on the kinds of the antimicrobial substance. Thus, it is necessary to obtain persistence of the antimicrobial property for more prolonged period of time.
The invention contemplates resolving these problems and thereby providing a medical device which has a physiological activity and which can maintain its antimicrobial activity stably for a prolonged period of time under physiological conditions, and a method for producing the medical device.
It is therefore an object of the present invention to solve the aforementioned problems of the prior art, and to thereby provide a medical device which simultaneously exhibits both excellent physiological and antimicrobial activity and a method for producing the same.
For the purpose of achieving the above object, the present inventors have conducted extensive studies and found as a result of their efforts, that a medical device which maintains its antimicrobial activity for a prolonged period of time even by indwelling under physiological conditions, can be obtained by reacting preferably from 0.5 to 10 mol % of acid anhydride groups in a high molecular weight substance having acid anhydride groups with a compound having two or more active hydrogen atoms in one molecule on a surface of the medical device, thereby forming and fixing a cross-linked coating film on the surface, and subsequently bonding a physiologically active substance and an antimicrobial substance to acid anhydride groups or carboxylate groups in the high molecular weight substance to thereby achieve the present invention.
Accordingly, a first embodiment of the invention relates to an antimicrobial medical device having physiological activity, which comprises a cross-linked coating film constituting a high molecular weight substance having acid anhydride groups formed on a surface of a base material, said cross-linked coating film is formed by reacting preferably from 0.5 to 10 mol % of the acid anhydride groups contained in the high molecular weight substance with a compound having two or more active hydrogen atoms in one molecule, and wherein a physiologically active substance and an antimicrobial substance are bonded to the cross-linked coating film.
Also, a second embodiment of the invention relates to a method for producing an antimicrobial medical device having physiological activity, which comprises forming a cross-linked coating film constituting a high molecular weight substance having acid anhydride groups on a surface of a base material of the medical device, by reacting preferably from 0.5 to 10 mol % of acid anhydride groups contained in the high molecular weight substance with a compound having two or more active hydrogen atoms in one molecule, and subsequently bonding a physiologically active substance and an antimicrobial substance to the cross-linked coating film.
According to the present invention, a medical device having functions of both physiological activity and antimicrobial activity can be obtained by a simple and easy method.
Other objects and advantages of the present invention will become apparent in view of the followed detailed description and working examples.